ES2402126T3 - Inhalable composition comprising nicotine - Google Patents

Abstract

An apparatus for the supply of nicotine containing an apparatus for the supply of nicotine containing: an inhalable composition; and means for iene: an inhalable composition; and means for supplying said composition to the nasal supply of said composition to the nasal or oral cavity of a user, the inhalable qu or oral composition of a user, the inhalable composition comprising: at least 22% by volume of oxygen comprises: at least 22% by volume of oxygen; and from 0.0005 to 5% w / w of nicotine or one; and from 0.0005 to 5% w / w of nicotine or a nicotine salt. nicotine salt

Description

Inhalable composition comprising nicotine

The present invention relates to a pressurized container comprising an inhalable composition comprising oxygen and nicotine or a salt or a derivative thereof, and to said inhalable composition. The present invention also relates to an apparatus for the delivery of nicotine comprising a housing containing the composition and means for supplying the composition to the nasal or oral cavity of a user.

Tobacco smoke contains nicotine, a well known stimulant. Nicotine is highly addictive and is the main reason why smokers find it difficult to quit smoking. The most damaging health effects of smoking, however, are attributable to substances that are formed during the combustion of tobacco, such as carbon monoxide and tar.

A certain number of products have been developed to help smokers quit smoking. For example, nicotine replacement therapies have been developed to provide physiologically acceptable alternatives to tobacco smoke. Examples of such therapies include nicotine patches for the skin for transdermal administration of nicotine and gum and dragees containing nicotine. These therapies, however, are limited by low nicotine absorption profiles. Subsequently, there is a growing need for nicotine supply systems that act more quickly and with better absorption profiles, as highlighted in a publication on tobacco limitation of the Government of Great Britain dated May 31, 2008. Especially, there is a the need for devices that stimulate the rapid absorption of nicotine in a pharmacokinetically similar way to tobacco cigarettes, and provide improved chemical formulations that reduce the damage and have a greater influence on the desire for the user to change smoking tobacco. With increasing restrictions for smoking cigarettes in public places, there are possibilities for a composition or device that can replace the physical act of smoking, and that is socially acceptable so that it can be used in all public places. In addition, there is a need for a device that can be used to dispense nicotine without smoking as a cigarette replacement, or to address nicotine dependence felt by smokers by helping them to quit smoking.

US Patent No. 5,167,242 describes an inhaler comprising a cylindrical cartridge containing a nicotine reservoir. The air inhaled through the cartridge is saturated with the nicotine in the reservoir. Therefore, when a user inhales air through the cartridge, he inhales a mixture of air and nicotine in his lungs. A disadvantage of the device is that there is a limit on the amount of nicotine that is administered through each inhalation. WO 2004/076289 attempts to address this problem by providing a container that allows a greater amount of air to be inhaled by inhalation. The container comprises a mass of fibers or filaments with a shape that provides reduced resistance to the flow of inhaled air through the container. The container may also contain additives, such as antioxidants, flavors and aromas. However, it has been discovered that the user still does not inhale enough nicotine by inhalation to provide the stimulant effect he achieves when he smokes. In addition, because this device is not pressurized, the device supplies most of the nicotine to the buccal and mucous cavities and does not generate an aerosol cloud with sufficient velocity in the inspiration flow so that the majority of the aerosol reaches the lungs. This results in a much longer period for nicotine to reach acceptable levels in blood plasma concentrations, typically 3-7 minutes instead of 7-14 seconds. Great Britain Patent No. 1528391 refers to aerosol compositions containing nicotine. United States Patent No. 2006/001884 A1 refers to an aerosolizable formulation comprising nicotine.

WO 01/49349 discloses an oxygen supply apparatus in which oxygen is stored in a cylinder which is also removed from the device and can be refilled or replaced. The apparatus supplies rapid or short inhalations of pure oxygen to the user to supplement the user's oxygen supply, for example, during exercise. There is no indication in this reference that the device can be used as a cigarette replacement, or to address nicotine dependence felt by smokers.

The present invention provides an apparatus according to claim 1 of the claims appended hereto.

According to a first reference example, a pressurized container is provided containing a composition comprising oxygen, nicotine or a nicotine derivative or a salt thereof, and a solvent, wherein the container is pressurized to at least 3 x 105Pa ( 3 bar), said container having an outlet valve that is selectively actuated to release the composition of the container.

According to a second reference example, an inhalable composition comprising at least 22% by volume of oxygen, and nicotine or a derivative or salt thereof is provided.

The composition contained in the apparatus of the present invention can be delivered to a user's nasal or oral cavity using any suitable apparatus. The composition is preferably dispensed in the form of a mixture of aerosolized particles. Preferably, the composition has a particle size distribution that is similar to tobacco smoke. The composition may have the appearance of steam or smoke.

The concentration of oxygen in the composition of the apparatus of the present invention is greater than the concentration of oxygen in the atmosphere. Therefore, the composition contained in the apparatus of the present invention provides an increased level of oxygen in combination with nicotine or a salt or a derivative thereof. The advantages of the composition are explained in more detail below.

Increased oxygen levels of the composition contained in the apparatus of the present invention can also increase the effectiveness of nicotine in its physiological functions. For example, it has been found that the psychoactive effect of nicotine increases when supplied with increased levels of oxygen. This provides the user with increased stimulation and, in particular, increased cognitive stimulation. It is known that oxygen influences dopamine, a neurotransmitter, which is believed to act in the same reward pathways as nicotine. It has been found that oxygen is especially useful as an adjuvant in nicotine replacement therapy.

With the use of increased oxygen levels, nicotine undergoes partial degradation and oxidation. This is usually associated with combustion in a tobacco cigarette. However, when nicotine is supplied with the increased oxygen levels of the present invention, it undergoes a similar reactive change. This is not only more acceptable to the user in terms of taste but, because the strong pH of some of the acidic nicotine salts used in the supply decreases, it also causes less irritation in the lung and bronchial tracts, particularly in the Mucosal and buccal tract.

The composition contained in the apparatus of the present invention can be used in a nicotine replacement therapy (NRT). For example, it can be given to NRT patients who are advanced smokers and manifest early or advanced phases of emphysema or chronic obstructive pulmonary disease (COPD). By using oxygen instead of air, patients can increase the rate of oxygen absorption. This can be beneficial for your respiratory patterns, allowing less dependence on the generation of deep inhalations. This is advantageous with respect to the nicotine delivered in air because the patient does not inhale so deeply to get his nicotine load, thereby reducing wheezing and / or COPD / asthma related attacks.

Increased oxygen levels of the composition contained in the apparatus of the present invention can also accelerate the rate of absorption and transport of nicotine through the blood. It is believed that increased oxygen levels cause a greater degree of oxygenation in the blood of a user by increasing plasma nicotine concentrations and therefore faster absorption through the blood brain barrier. This increases the speed and efficiency with which nicotine reaches the receptors (for example, nicotinic acetylcholine receptors) in the brain, thereby improving the directional potential of nicotine as a replacement drug. In preferred embodiments, the composition contained in the apparatus of the present invention can deliver less nicotine per unit volume of inhalation, but can still achieve equal, similar or improved satisfaction of the nicotine craving for the user. This can be useful because a lower dose of nicotine helps the user avoid some of the most dangerous vasoconstrictor effects of nicotine.

The composition contained in the apparatus of the present invention can also be used for the treatment of diseases such as neurodegenerative diseases such as Alzheimer's or Parkinson's disease. It is believed that the increased level of oxygen enriches the flow of oxygenated blood in the extremities of the brain. Increased blood flow and widening of the capillaries in the extremities of the brain allow nicotine more contact with the receptors, thereby increasing the effectiveness of beneficial psychoactive action on the neurotransmitters of the brain. This effect may increase when additives, such as gingko and gingko extracts, are included in the composition. In a preferred embodiment, therefore, the composition additionally includes gingko and / or a gingko derivative.

The composition contained in the apparatus of the present invention provides better anxiolytic effects than those achieved with conventional nicotine delivery methods. Accordingly, the composition contained in the apparatus of the present invention can be used to reduce tension, irritability and stress.

Preferably, the composition contained in the apparatus according to the present invention comprises at least 30% by volume, more preferably at least 50% by volume, even more preferably at least 60% by volume of oxygen. For example, the composition may comprise at least 70% by volume or at least 80% by volume of oxygen. In one embodiment, the composition includes more than 90% by volume of oxygen.

The oxygen of the composition can be supplied from a pressurized source of basically pure gaseous oxygen. For example, oxygen can be supplied from a source of at least 95% by volume, preferably at least 97% by volume of oxygen. The oxygen can be stored in a pressurized container, either in a conventional cylinder or in a bag with a valve. Alternative

or additionally, oxygen can be generated, for example, by a chemical reaction. For example, oxygen can also be generated chemically from an oxygen source, such as an inorganic chlorate or perchlorate. Preferably, sodium chlorate is used. The chemical generation of oxygen can be triggered by an ignition source, such as a spark or an electric current. The oxygen source can also be turned on mechanically, for example, with an impact using a hammer.

In one embodiment, sodium chlorate granules are placed very close to the nicotine particles, occasionally with a thin barrier positioned between them. Once it has been turned on, the sodium chlorate reacts with an exothermic reaction to produce oxygen. The heat generated by the reaction can be used to vaporize nicotine and, occasionally, other additives in the composition. Nicotine vapor and oxygen can be supplied to the user using any suitable apparatus. For example, the apparatus can be provided with a protective heat barrier and a semipermeable filter. Therefore, when the composition is inhaled through the apparatus, for example, through a mouthpiece, the composition is cooled and filtered before delivery.

Alternatively, electrochemical oxygen generation is possible. For example, a catalyst, such as a cobalt chelate, can be used to store oxygen, and release it when activated by an electric current. This electric current can activate a microprocessor attached to an atomizer that could aerosolize a mixture of nicotine and solutions located within the device. Both oxygen and aerosolized vapor can be extracted from the device by breathing the user over the mouthpiece.

The composition may include less than 75% by volume of nitrogen. Preferably, the composition comprises less than 60% by volume, more preferably less than 50% by volume of nitrogen. In one embodiment, the composition comprises less than 30% by volume of nitrogen.

The composition may include less than 5% by volume of carbon dioxide and / or carbon monoxide. Preferably as the composition includes less than 2% by volume, more preferably less than 0.5% by volume, even more preferably less than 0.04% by volume of carbon dioxide and / or carbon monoxide. In a preferred embodiment, carbon monoxide and / or carbon dioxide are basically absent from the composition.

The composition includes nicotine or a salt thereof with a concentration of 0.0005 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w . In preferred embodiments, the composition includes 0.01% w / w, 0.1% w / w or 1% w / w nicotine / nicotine salt.

Optimally, for every 6.6 g of pressurized oxygen, 0.01 to 0.5 g of nicotine, preferably 0.06 to 0.2 g of nicotine (or its salt) are used. The precise amount of nicotine or its salt used may depend on the nature of the source of nicotine used. In the case of a nicotine salt having a 1: 1 molar acid ratio, 0.06 g of nicotine can be used for every 6.6 g of pressurized oxygen. This amount of nicotine can be increased if the molar ratio of salt acid is higher. For example, when the acidic molar ratio of the nicotine salt is 2: 1 (for example, in the nicotine salts of lauric, citric, or malic acid), 0.12 g of nicotine can be used per 6.6 g of pressurized oxygen. When the molar ratio of nicotine salt acid is 3: 1 (for example, in nicotine salts of propionic acid), 0.12 g of nicotine can be used for every 6.6 g of pressurized oxygen.

Any suitable source of nicotine can be used. For example, nicotine may be the base of nicotine free, and / or a nicotine salt. When the nicotine free base is used, it can be used in liquid form. When a nicotine salt is used, it can be used in the form of a solution. Suitable solvents for such solutions include alcohols, glycols and glycol ethers. Specific examples include propylene glycol, polypropylene glycol, polyethylene glycol (PEG), glycerol, ethanol and propanol. Preferably the solvent is polyethylene glycol, and / or propylene glycol. More preferably the solvent is propylene glycol. In a preferred embodiment the solvent comprises ethanol and propylene glycol. The solvent may be present in amounts of 0.1 to 20% w / w, preferably 1 to 10% w / w. Preferably nicotine is present in the composition in liquid form.

Suitable nicotine salts include salts formed from the following acids: acetic, propionic, 1,2butyric, methylbutyric, valeric, lauric, palmitic, tartaric, citric, malic, oxalic, benzoic, alginic, hydrochloric, chloroplatinic, silicotungstic, pyruvic , glutamic and aspartic. Other nicotine salts, such as dehydrated nicotine bitartrate, can also be used. Mixtures that two or more nicotine salts can be used.

The composition may also include an antioxidant. One or more antioxidants can be used. The precise amount of antioxidant used may vary depending on the nature of the antioxidant used. The antioxidant may be present in an amount of 0.0001 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w of the composition. In a preferred embodiment, the proportion of nicotine (or salt or derivative thereof) with respect to the antioxidant is at least 1.5: 1. The proportion of nicotine (or salt or derivative thereof) with respect to the antioxidant may be 2: 1 or more; 3: 1 or more; 4: 1 or more; 5: 1 or more; or even 10: 1 or more.

When antioxidants, such as carotenoids, are included in the composition, they may experience partial degradation in a process similar to carotenoid degradation in tobacco smoke, and therefore have similar taste. This makes the composition attractive to the user.

Suitable antioxidants include phenolic compounds, flavonols, flavanones, flavones, flavon-3-oles, anthocyanins (flavonal), isoflavones, cumestanes, carotenes, xanthophiles, phytosterols and tocopherols.

Suitable phenolic compounds include monophenols, apiol, carnosol, carvacrol, dilapiol, rosemarinol and flavonoids (polyphenols).

Suitable flavonols include quercetin, gingerol, kaempferol, myricetin, resveratrol and isoramnetine.

Suitable flavanones include hesperidin, naringenin, silybin and eriodictiol.

Suitable flavones include apigenin, tangeritin and luteolin.

Suitable flavan-3-oles include catechins, catechin, gallocatechin, epicatechin, epigallocatechin, epicatechin 3galate, epigallocatechin 3-gallate, teaflavin, 3-teaflavine gallate, teaflavin 3-gallate, 3,3 'teaflavin digalate and tearubigins.

Suitable (flavonal) anthocyanins include pelargonidine, peonidine, cyanidine, delfinidine, malvidin and petunidine.

Suitable isoflavones (phytoestrogens) include daidzein (formononetin).

Suitable cumestanes (phytoestrogens) include cumestrol, ellagic acid, gallic acid, salicylic acid, tannic acid, vanillin, capsaicin, curcumin (oxidizes to vanillin), hydroxycinnamic acids, caffeic acid, chlorogenic acid, cinnamic acid, ferulic acid, coumarin, lignans (phytoestrogens), silymarin and matairesinol, secoisolariciresinol, terpenes (isoprenoids) and carotenoids (tetraterpenoids).

Suitable carotenes (orange pigments) include alpha carotene, beta carotene, gamma carotene, delta carotene, lycopene, neurosporene, phytophene and phytoen.

Suitable xanthophils (yellow pigments) include cantaxanthin, cryptoxanthin, zeaxanthin, astaxanthin, lutein, monoterpenes, limonene, perilyl alcohol and saponins.

Suitable phytosterols include campesterol, beta sitosterol, gamma sitosterol and stigmasterol.

Omega-3,6,9 fatty acids can also be used as an antioxidant component.

The composition may also include an essential oil. The essential oil may be present in an amount of 0.0001 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w of the composition.

Suitable essential oils include geraniol, nerol, phenethyl alcohol, eugenol methyl ether, farnesol, linalool, citronellol, rose, cuminaldehyde, zingiberene, farnesol, verbenone, nootkatone, myrcene, menthol, citral, citronellol, citronelal, geraniol, nerol, linalo pinene, thymol and chin.

The essential oil can be obtained by any suitable means, including distillation, solvent extraction and cold expression.

The composition may include an aroma component. The precise amount of aroma components used may depend on the nature of the aroma components. The aroma or aromas may be present in an amount of 0.0001 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w of the composition . In a preferred embodiment, the proportion of nicotine (or salt or derivative thereof) with respect to the aroma component is at least 1.5: 1. The proportion of nicotine (or salt or derivative thereof) with respect to the aroma component may be 2: 1 or more; 3: 1 or more;

4: 1 or more; 5: 1 or more; or even 10: 1 or more.

Suitable aroma components include aromas derived from flowers, leaves or fruits. Preferably, the aroma components are aroma components that are typically added to tobacco products (eg, accredited aroma components). Specific examples include apple juice concentrate, apricot extract, asafetida, basil oil, balm and Peruvian oil, angelica root extract, bay leaf sweet oil, bergamot oil, blackcurrant sprout absolute, beet juice concentrate, buchu leaf oil, cananga oil, caraway oil, locust bean extract, beta-carotene, cardamom oleoresin, locust bean extract and extract, carrot oil, cassia bark oil, cassia oil husk, chicory extract, chocolate, cinnamon leaf oil, citronella oil, coriander oil and extract, coffee, green and white cognac oil, cubeb oil, costus root oil, solid tooth root extract lion, davana oil, sweet fennel oil, fenugreek extract, fig juice concentrate, galbanum oil, gentiana root extract, germany rose oil, ginger oil and oleoresin, g ammonia licirricin, grape juice concentrate, honey, hops oil, hyssop oil, absolute concentrate and jasmine oil, lavender oil, lemon oil and extract, citronella oil, root, fluid extract and licorice powder, oil of lime, monte celery oil, mace powder, tangerine oil, maple syrup and concentrate, mate leaf, menthol, malt extract, maltol, molasses extract and tincture, oak moss absolute, verbascum flowers , myrrh oil, nutmeg oil and powder, oak moss absolute, orange blossom water, orange oil, oregano oil, root extract and concentrated orris oil, palmarosa oil, parsley seed oil , pepper oil, peppermint oil, pepper leaf oil, pineapple juice concentrate, pine needle oil, plum juice, prune juice, raisin juice (concentrates), absolute and rose oil, rye extract, rosemary oil, sandal oil Lo, peppermint oil, sugars, thyme oil, tocopherols, vanillin, wheat extract, wild beer bark extract and violet leaf absolute.

The composition may also comprise a flavor component. The flavor component or components may be present in the amount of 0.0001 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w of the composition.

Suitable flavor components include flavor components typically added to tobacco products. Examples include carotenoid products, alkenols, aldehydes, esters and flavor constituents of delta-lactone.

Suitable carotenoid products include beta ionone, alpha ionone, beta-damascone, beta-damascenone, oxoedulane I, oxo-edulane II, teaspirone, 4-oxo-beta-ionone, 3-oxo-alpha-ionone, dihydroactinodiolide, 4-oxoisophorone , safranal, and beta-cyclocitral.

Suitable alkenols include C4 to C10 alkenols, preferably C5 to C8 alkenols. Specific examples include: cis-2-Penten-1-ol, cis-2-Hexen-1-ol, trans-2-Hexen-1-ol, trans-2-Hexen-1-ol, cis-3-Hexen -1-ol, trans-3-Hexen-1-ol, trans-2-Hepten-1-ol, cis-3-Hepten-1-ol, trans-3-Hepten-1-ol, cis-4-Hepten -1-ol, trans-2-Octen-1ol, cis-3-Octen-1-ol, cis-5-Octen-1-ol, 1-Octen-3-ol and 3-Octen-2-ol.

Suitable aldehydes include benzaldehyde, glucose and cinnamaldehyde.

Suitable esters include allyl hexanoate, benzyl acetate, bornyl acetate, butyl butyrate, ethyl butyrate, ethyl hexanoate, ethyl cinnamate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, nonanoate ethyl, ethyl valerate, geranyl acetate, geranyl butyrate, isobutyl acetate, isobutyl formate, isoamyl acetate, iso-propyl acetate, linalyl acetate, linalyl butyrate, linalyl formate, methyl acetate, anthranilate methyl, methyl benzoate, benzyl and methyl acetate, methyl butyrate, methyl cinnamate, methyl pentanoate, phenyl and methyl acetate, methyl salicylate (gaulteria oil), nonyl caprylate, octyl acetate, octyl butyrate , amyl acetate (pentyl acetate), pentyl hexanoate, pentyl pentanoate, propyl ethanoate, propyl isobutyrate, terpenyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, ethyl valerate, ethyl hexanoate, ethyl heptanoate, ethyl octanoate, ethyl nonanoate, ethyl decanoate, ethyl dodecanoate, ethyl myristate, and ethyl palmitate.

Suitable delta-lactone flavor constituents include delta-Hexalactone, delta-Octalactone, delta-Nonalactone, delta-Decalactone, delta-Undecalactone, delta-Dodecalactone, Massoia lactone, Jasmine lactone and 6-Pentyl-alpha-pyrone.

The composition preferably includes a solvent. Suitable solvents include alcohols, glycols and glycol ethers. Specific examples include propylene glycol, polypropylene glycol, polyethylene glycol (PEG), glycerol, ethanol and propanol. Preferably the solvent is polyethylene glycol (for example, PEG 400) and / or propylene glycol. More preferably the solvent is propylene glycol.

The present inventors have discovered that propylene glycol is the preferred solvent because it provides better atomization characteristics to the aerosol cloud compared to other solvents. As a consequence of the nature of propylene glycol, they can be obtained in small diameter aerosol drops, typically 5 micrometers, helping lung delivery and deposition in the lungs. This means that the absorption profile is faster and more effective than if larger diameter aerosol drops were formed. Similarly, because the aerosol is thinner using propylene glycol as a solvent, users may experience a mist or vapor that is similar in appearance to smoke.

In one embodiment the solvent may be ethanol and propylene glycol. This also allows a small spray droplet size to be formed helping to better deposition and distribution.

The solvent may be present in amounts of 0.1 to 20% w / w, preferably 1 to 10% w / w. Mixtures of two or more solvents can also be used.

The composition may include cognitive enhancement additives, such as star anise, caffeine, chamomile flower oil, coconut extract, sage oil, eucalyptol, kola nut extract, powder and valerian root extract, green tea, tea oolong, ginkgolides, ginsenosides, taurine, artemisinin, echinacea, grapefruit mercaptan, lemon oil, cinnamon, tertrahydrocannabinol, cannabidiol and cannabinol. It is believed that such cognitive enhancement additives stimulate human cognitive ability, that is, the functions and abilities of the brain. In addition, some of these additives have separate functions, such as antioxidant, aroma, flavor and / or anticarcinogenic functions.

Such cognitive additives may be present in an amount of 0.0001 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w of the composition.

Other optional components include bronchodilators, such as opiopogon, glycyrrhizin and theophylline. When used, the bronchodilator may be present in an amount of 0.0001 to 5% w / w, preferably 0.001 to 2% w / w, more preferably 0.001 to 1% w / w of the composition. The proportion of nicotine (or salt or derivative thereof) with respect to the bronchodilator may be 20: 1 or less, for example, 10: 1. When glycyrrhizine is used, the proportion of nicotine (or salt or derivative thereof) with respect to glycyrrhizin can be 5: 1.

The composition may also include sweeteners, such as natural sugars. Examples include dextrose, fructose, and glucose. Sugar alcohols, such as sorbitol, xylitol and glycerol, can also be used. Artificial sweeteners can also be used. Examples include saccharin and its sodium and calcium salts and phenylalanine. When used, the sweeteners may be present in an amount of 0.1 to 5% by volume of the composition, for example, 2 to 3% by volume of the composition.

The composition may include stabilizing and / or health enhancing additives, such as vitamins, including vitamin A and C and tocopherols, as well as vitamin D and B12. When employed, such additives may be present in an amount of 0.1 to 5% by volume of the composition.

For the avoidance of doubt, it should be noted that while certain additives have been classified into specific categories, certain additives may have more than one function. For example, in addition to acting as cognitive enhancement additives, additives such as green tea may also have anticarcinogenic properties.

The volume ratio of oxygen with respect to nicotine (or a salt or a derivative thereof) in the composition of the second aspect of the present invention is at least 1: 1, preferably at least 2: 1, for example, from 1: 1 to 3: 1.

The pH of the composition is preferably 5 to 8, more preferably 6 to 7.5, for example approximately 7. A highly acidic and highly alkaline pH should be avoided to reduce irritation of the mucosa cavity.

The composition may be at least partially hygroscopic. This gives the composition the ability to attract water molecules from the surrounding environment either by absorption or by adsorption. A certain degree of hygroscopicity is desirable since it allows the composition to deposit a little further in the airways and reduces the risk of irritation of the glottis.

In a preferred embodiment, the composition comprises:

oxygen,

liquid nicotine or a nicotine salt thereof, and, optionally, at least one of an antioxidant,

a scent,

a component of flavor,

a propellant,

a cognitive potentiating additive, and a solvent.

More preferably, the composition comprises

oxygen,

liquid nicotine or a nicotine derivative or a salt thereof,

an antioxidant, a solvent, and

a scent

The use of oxygen can also be beneficial when additives, such as antioxidants and anticarcinogenic compounds, are provided due to the increased transport efficiency of these molecules in the oxygen-enriched blood.

According to a reference example, a pressurized container is provided comprising the composition contained in the apparatus of the present invention.

In one embodiment of the reference example, the composition in the pressurized container is a composition according to that contained in the apparatus of the present invention. Alternatively, the composition in the pressurized container may be a composition (for example, an inhalable composition) comprising oxygen in an amount of less than 22% by volume, and nicotine or a derivative or salt thereof, and a solvent In one embodiment, the composition contains oxygen in an amount of less than 20% by volume, for example, less than 15% by volume. In another embodiment, the composition contained in the pressurized container comprises oxygen in an amount of at least 1% by volume, at least 2% by volume, at least 5% by volume,

or at least 10% by volume. In another embodiment, the pressurized container contains oxygen in an amount of at least 1% by volume, at least 2% by volume, at least 5% by volume, at least 10% by volume, at least 30% in volume or at least 50% in volume. In another embodiment, the composition may contain pressurized air and nicotine or a salt or a derivative thereof. For the avoidance of doubt, optional additives that may be present in the composition of the second aspect of the present invention may be present, for example, in corresponding amounts in the composition comprising oxygen in an amount of less than 22% by volume. , and nicotine or a derivative or salt thereof.

The pressurized container of the reference example or contained in the apparatus of the present invention can be used to release a gaseous flow of oxygen and liquid nicotine to a user. For example, the pressurized container can be provided with means for supplying the contents of the container to a user's nasal or oral cavity. Such means may take the form of a button, actuator or mechanism activated by breathing. The pressurized container can be used to deliver an unmeasured dose of nicotine to the user. This can be advantageous over the prior art methods of NRT, such as inhalers, nasal sprays, dragees and conventional patches currently available in the market, because they can allow autonomy in the regulation of nicotine replacement, since in this the User can regulate the amount of nicotine composition he wants to inhale. Alternatively or additionally, the pressurized container can be used to deliver a measured dose of nicotine to the user. This can be advantageous so that the user can monitor nicotine uptake.

The pressurized container contained in the apparatus of the present invention can be used to release a gaseous flow of oxygen and liquid nicotine to the user without the need for a separate source of energy. For example, the composition can be released without requiring the heating of the substrates, the combustion of the material or an electric current generated by a battery. Although the container may include an additional propellant (see below), this is not essential for the release of the composition.

The pressurized container of the present invention can be used in nicotine replacement therapy (NRT). For example, it can be used to deliver nicotine to NRT patients who are advanced smokers and manifest early or advanced phases of emphysema or chronic obstructive pulmonary disease (COPD). By supplying pressurized oxygen with nicotine, the patient is required to make a less effort in inhalation than with a conventional nicotine inhaler, reducing the risk of the patient becoming out of breath. In addition, because oxygen flow can be basically constant, users will not have problems associated with dose coordination.

Another advantage of the pressurized container contained in the apparatus of the present invention is that it is physiologically more beneficial than conventional TRN products. It is known that nicotine is a neuroprotector, which has stress relief properties. When oxygen and nicotine are used together and administered by a pressurized cylinder, both combine to form a physiologically beneficial inhalation that is more nuanced and more potent stress reliever. In addition, the addition of nicotine can act as a neuroprotector against increased levels of oxygen and glucose in the brain. Oxygen also targets the same receptors that nicotine occupies and is especially useful as an adjuvant for nicotine replacement therapy.

In the pressurized container contained in the apparatus of the present invention, oxygen is stored with pressure nicotine. As a consequence, the user of a pressurized container with oxygen and nicotine may experience the taste of nicotine that has undergone partial oxidation, giving more similarity to the taste of a tobacco cigarette. Similarly, with a pressurized container, you can feel the constant and consistent flow of oxygen and nicotine in the oral and oral cavities, and especially in the glottis and upper throat. This is a pleasant reproduction of the smoke felt in these areas after the inhalation of a tobacco cigarette.

An additional advantage of storing the nicotine under pressure with oxygen is that there is no risk of liquid nicotine or nicotine particles evaporating to the surrounding environment. This is a problem with nicotine capsules or cartridges used in conventional TRN inhalers, which loses their strength and intensity when nicotine is exposed to the outside environment. In the pressurized container there is no contact with oxygen or ambient air, and therefore the mixture provides a more accurate and consistent dosage.

The pressurized container contained in the apparatus of the present invention can take the form of a pressurized cylinder, for example, a pressurized aluminum cylinder. The bottle can be completely recyclable and / or reusable. The bottle can be filled as required by a vending machine or a larger container containing the desired composition with a high pressure gradient. In one embodiment, the bottle is a 304L aluminum bottle. In another it can be a standard aluminum cylinder that can come from Aerocan, Cebal, 3M or others. In a further embodiment, the bottle can be made of PET.

The pressurized container may be pressurized at a pressure of 3 x 105 Pa at 1.5 x 107 Pa (3 to 150 bar), preferably 5 x 105 Pa to 2 x 106 Pa (5 to 20 bar), more preferably 5 , 5 x 105 Pa at 1 x 106 Pa (5.5 to 10 bar), most preferably at about 6 x 105 Pa (6 bar).

The pressurized container may be able to dispense the composition in the form of an aerosolized solution mixture. Preferably, the mixture has a particle size distribution that is similar to tobacco smoke. The mixture may have the appearance of steam or smoke.

The average droplet size in the mixture is preferably 1 to 40 micrometers, preferably 2 to 10 micrometers, most preferably about 5 micrometers.

The composition may additionally include a propellant as such as a hydrofluorocarbon, preferably a hydrofluoroalkane. Suitable propellants include 1,1,2,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3heptafluoropropane (HFC-227). Preferably the propellant is liquefied. The pressurized container may contain an oxygen propellant either in the bottle or externally using a valve bag system.

The composition may comprise at least 1% by volume of propellant. Preferably, the composition comprises at least 10% by volume of propellant, more preferably at least 30% by volume. In one embodiment the composition comprises more than 50% by volume propellant.

In the pressurized container of the present invention the solvent contained therein is preferably an alcohol, a glycol and / or a glycol ether. Specific examples include propylene glycol, polypropylene glycol, polyethylene glycol (PEG), glycerol, ethanol and propanol. Preferably the solvent is polyethylene glycol (for example, PEG 400) and / or propylene glycol. More preferably the solvent is propylene glycol.

The present inventors have discovered that propylene glycol is the preferred solvent because it provides better atomization characteristics to the aerosol cloud compared to other solvents. As a consequence of the nature of propylene glycol, small diameter aerosol drops, typically 5 micrometers, can be achieved, aiding lung delivery and deposition in the lungs. This means that the absorption profile is faster and more effective than when aerosol drops of larger diameters are formed. Similarly, because the aerosol is thinner with the use of propylene glycol, users may experience a fog or vapor that is similar in appearance to smoke.

In one embodiment the solvent may be ethanol and propylene glycol. This also allows a small spray droplet size to be formed helping to better deposition and distribution.

The solvent may be present in amounts of 0.1 to 20% w / w, preferably 1 to 10% w / w. Mixtures of two or more solvents can also be used.

In an embodiment of a reference example the pressurized container comprises:

at least 1% by volume of oxygen;

a nicotine, a nicotine derivative or a salt thereof;

a solvent and

at least 30% by volume of a propellant.

In this embodiment the nicotine is preferably in liquid form. The solvent is preferably propylene glycol and / or ethanol. The propellant is preferably a hydrofluoroalkane.

In another embodiment of a reference example the pressurized container comprises:

at least 10% by volume of oxygen; a nicotine, a nicotine derivative or a salt thereof;

a solvent and

at least 20% by volume of a propellant.

In this embodiment the nicotine is preferably in liquid form. The solvent is preferably propylene glycol and / or ethanol. The propellant is preferably a hydrofluoroalkane.

In a further embodiment of the present invention the pressurized container comprises:

at least 22% by volume of oxygen;

a nicotine, or a salt thereof;

a solvent and

at least 10% by volume of a propellant.

In this embodiment the nicotine is preferably in liquid form. The solvent is preferably propylene glycol and / or ethanol. The propellant is preferably a hydrofluoroalkane.

The container may be pressurized at a pressure of 3 x 1.05 Pa at 1.5 x 107 Pa (3 to 150 bar), preferably 5 x 105 Pa at 2 x 106 Pa (5 to 20 bar), more preferably of 5.5 x 105 Pa at 1 x 106 Pa (5.5 at 10 bar), most preferably at about 6 x 105 Pa (6 bar). The pressurized container can be provided with a valve that can be operated to deliver the composition into a user's nasal or oral cavity, for example, in the form of a mixture of aerosolized particles. This mixture may have the appearance of smoke or steam. Because the composition is pressurized, the aerosolized mixture can be produced without the need for a separate energy source. As the pressure of the container decreases, the rate of release of the composition of the container may also decrease, reproducing the nicotine drop that occurs in each inhalation of a tobacco cigarette.

In an alternative embodiment, the composition contained in the apparatus of the present invention is generated in situ within the apparatus. For example, the apparatus may include a first reservoir containing oxygen, and a second reservoir containing nicotine or a derivative or salt thereof, and means for mixing said oxygen with said nicotine or derivative or salt thereof to produce the composition contained in the apparatus of the present invention.

The first reservoir can be in the form of a pressurized oxygen container. The container may contain a gas comprising at least 30% by volume of oxygen, preferably at least 50% by volume, more preferably at least 70% by volume, and most preferably at least 90% by volume of oxygen . In a preferred embodiment the container contains basically pure gaseous oxygen.

The second reservoir preferably contains nicotine or the derivative, or the salt thereof in liquid form or in solution, optionally with optional additives and components, and may contain solvent and propellant.

The first reservoir can be provided with a valve, which is actuated to allow oxygen from the first reservoir to pass through the contents of the second reservoir to produce in situ the composition of the second aspect of the present invention. Alternatively, the first reservoir and the second reservoir are provided with their respective valves, which are actuated to allow the contents of the first and second reservoir to flow into a mixing chamber where the composition contained in the apparatus is produced in situ. The present invention. The composition produced is supplied to the nasal or oral cavity of a user, for example, in the form of a mixture of aerosolized particles. This mixture may have the appearance of smoke or steam. Because pressurized oxygen is used to produce the composition, the aerosolized mixture can be produced without the need for a separate energy source.

In another alternative embodiment, the apparatus comprises means for the generation of oxygen, a reservoir containing nicotine or a derivative or a nicotine salt, and means for mixing the oxygen generated with said nicotine or derivative or salt thereof to produce the Composition of the present invention. As explained above, the means for generating oxygen can take the form of an electrochemical cell. Alternatively, oxygen can be chemically generated from an oxygen source, such as a chlorate

or an inorganic perchlorate. The oxygen generated is used to produce in situ the composition contained in the apparatus of the present invention. To ensure that the composition is supplied in the form of a mixture of aerosolized particles, the apparatus can be additionally provided with a microprocessor, such as a microprocessor powered by a battery, to generate the desired smoke or vapor effect.

The apparatus can be provided with a filter or an atomizer to aid dispersion of the composition of the present invention.

The apparatus can also be provided with a heating element to heat the composition before delivery.

The apparatus can also be provided with, for example, a heat barrier to reduce the temperature of the composition before it reaches the user's nasal or oral cavity, if necessary.

Preferably, the apparatus takes the form of a simulated cigarette device comprising an elongated housing having an inhalation outlet port (for example, a mouthpiece) at one end and a reservoir that extends along a considerable part of accommodation. In housing it preferably has an outlet valve adjacent to the inhalation outlet port, which is actuated to allow the contents of the reservoir to pass from the reservoir and out of the inhalation outlet port. The outlet valve can be activated by breathing

or it can be operated by mechanical means.

In a preferred embodiment, the reservoir contains the composition of the second aspect of the present invention. For example, the reservoir can be a pressurized container containing the composition of the second aspect of the present invention.

Alternatively, the reservoir may contain oxygen. For example, the reservoir can take the form of a pressurized container containing at least 30% by volume of oxygen, preferably at least 50% by volume, more preferably at least 70% by volume, and even more preferably at least 90% by volume of oxygen. The pressurized container may be pressurized at a pressure of 3 x 105 Pa at 1.5 x 107 Pa (3 to 150 bar), preferably 5 x 105 Pa to 2 x 106 Pa (5 to 20 bar), more preferably 5 , 5 x105 Pa at 1 x106 Pa (5.5 to 10 bar), most preferably at about 6 x 105 Pa (6 bar). In this embodiment, the cigarette device may additionally include a second tank containing nicotine (or a salt or a derivative thereof), optionally together with the additives and optional components mentioned above. The oxygen-containing reservoir can be provided with a valve, which is actuated to allow oxygen to pass through the contents of the second reservoir to produce in situ the composition of the second aspect of the present invention. Alternatively, the oxygen-containing reservoir and the second reservoir are provided with their respective valves, which are actuated to allow the contents of the reservoirs to flow into a mixing chamber where the composition of the second aspect of the present is produced in situ. invention. In the case of the simulated cigarette device, the elongated housing can be provided with a filler inlet port and the reservoir can be provided with a filler valve adjacent to the filler inlet port. The filling unit may include a composition or oxygen reservoir having an outlet port and an associated outlet valve. The filler valve of the cigarette device may be arranged to be operated in conjunction with the outlet valve of the filler unit to open a flow path from the filler unit reservoir to the reservoir of the cigarette device. The oxygen in the oxygen reservoir of the filling unit can be generated in situ, for example, by chemical or electrochemical means.

By providing a cigarette device that is refillable from a filler unit that is itself refillable, the present invention provides a user-friendly system. The cigarette device can be manufactured about the size of a known smoking product such as a cigarette or cigar, while the filling unit can also be easily portable. For example, it can be of a size comparable to a pack of cigarettes. Therefore the user is able to carry the cigarette device and the filling unit with the same comfort with which it carries a pack of cigarettes.

A combination of the cigarette device and the filling unit may have sufficient capacity to last for a certain number of days of normal use before the filling unit needs to be filled. The tank from which the filling unit itself is filled could be, for example, a dispensing machine, or a high pressure cylinder that the user can have at home or in his car so that he does not always have to carry it with him .

Details of the types of apparatus that can be used to deliver the composition of the present invention are provided, by way of example, in the Applicant's related patent applications, with UK patent application numbers 0712304.5, 0712305.2 and 0712306.0.

Example 1

A composition was prepared by mixing the following components:

Nicotine - 0.03 g

Oxygen - 0.03 g

Aromas- 0.01 g

Ethanol - 0.048 g

Propylene Glycol - 14.91 g

HFA134a - 18.39 g

Menthol - 0.01 g

Eucalyptus - 0.01 g

Citronellol - 0.01 g in a pressurized container at 3.7 x 105 Pa (3.7 bar).

Example 2

A composition was prepared by mixing the following components:

Nicotine - 0.03 g Oxygen - 2.75 g Aromas - 0.01 g Ethanol - 0.048 g Propylene Glycol - 9.84 g Vanilla Extract - 0.01 g Coconut Extract - 0.01 g Green Tea Extract - 0.01 g Echinacea Extract - 0.01 g

in a pressurized container at 1.22 x 106 Pa (12.2 bar).

Example 3

A composition was prepared by mixing the following components:

Nicotine - 0.03 g Oxygen - 0.03 g Aromas - 0.01 g Ethanol - 0.048 g Propylene Glycol - 14.91 g HFA134a - 18.39 g

in a pressurized container at 3.7 x 105 Pa (3.7 bar).

Example 4

A composition was prepared by mixing the following components:

Nicotine - 0.03 g Oxygen - 2.75 g Aromas - 0.01 g Ethanol - 0.048 g Propylene Glycol - 9.84 g HFA134a - 12.14 g

in a pressurized container at 1.22 x 106 Pa (12.2 bar).

Example 5

A composition was prepared by mixing the following components:

Nicotine - 0.03 g Oxygen - 6.6 g Aromas - 0.01 g Ethanol - 0.048 g Propylene Glycol - 4.97 g HFA134a - 6.06 g

in a pressurized container of 2.2 x 106 Pa (22 bar).

Example 6

A composition was prepared by mixing the following components:

6.6 g of oxygen 0.18 g of nicotine-free base 2.5 g of polyethylene glycol 0.45 g of green tea extract 0.45 g oolong tea extract

0.18 g of Echinacea extract 0.3 g of lemon oil 0.18 of coconut extract 0.18 g of cinnamon oil 0.18 g glycyrrhizin.

Claims (9)

one.

 An apparatus for the supply of nicotine containing:

an inhalable composition; Y means for supplying said composition to the nasal or oral cavity of a user, the inhalable composition comprising: at least 22% by volume of oxygen; Y from 0.0005 to 5% w / w of nicotine or a nicotine salt.

2.

 An apparatus as claimed in claim 1, wherein the composition is contained in a pressurized container.

3.

 The apparatus as claimed in claim 2 wherein the container is pressurized to at least 3 x 105 Pa.

Four.

 The apparatus as claimed in any preceding claim, wherein the composition further comprises a solvent, preferably an alcohol, glycol or glycol ether solvent.

5.

 The apparatus as claimed in any preceding claim, wherein the composition further comprises an antioxidant and / or a cognitive potentiating additive, and / or an essential oil, and / or a flavor and / or aroma component.

6.

 The apparatus as claimed in any preceding claim wherein the composition comprises a hydrofluoroalkane propellant.

7.

 An apparatus as claimed in claim 1, comprising:

a first reservoir that contains oxygen, a second reservoir containing nicotine or a derivative or a nicotine salt, and means for mixing said oxygen with said nicotine or derivative or nicotine salt to produce the composition.

8.

 An apparatus as claimed in claim 1, comprising:

means for oxygen generation, a first deposit containing nicotine or a derivative or a nicotine salt, and means for mixing the oxygen generated with said nicotine or derivative or nicotine salt to produce the composition.

9.

 An apparatus as claimed in any preceding claim, which is in the form of a simulated cigarette.